Despite need for consistent adherence to medical care, youth living with HIV (YLWH) have low rates of adherence and retention in care, and are at great risk for being lost to follow-up.(5,16-18) There is a great need for adherence interventions that are novel and appealing for YLWH.(7,8,14) We developed, and preliminarily examined, a multi-level technology that integrates a 7-day smart medication device (Wisepill) WITH an immersive and appealing smartphone app/game that is attractive and engaging for YLWH.(82,83) During gameplay, YLWH fight HIV in colorful and immersive organ systems, and receive adherence related text messages with game graphics. Wisepill openings guide game-related text messages and can result in bonus points in the app/game. We tested the Multilevel Gaming Intervention in a developmental trial. The impact of the intervention was greatest among those who had newly begun ART. In participants who had newly begun ART, the intervention decreased viral load and improved ART adherence. Those newly starting ART in the intervention, compared to those newly starting ART in the control, experienced a 0.96 log viral load greater decrease and evidenced a large effect size for improved adherence as measured by Wisepill (d=1.18, 71% vs. 48% adherence at post-test). These interactions between intervention and newly starting ART were significant in ANCOVAs, accounting for baseline values (viral load: F=4.33, p=0.04, adherence: F=3.20, p=0.05). For this next proposed stage of research, we will further test the Multilevel Gaming Intervention with YLWH who are newly starting ART at clinical sites in New England and in Mississippi. A multisite randomized controlled study (48 weeks) among 120 YLWH newly starting ART will test the efficacy of the intervention compared to a control condition (who receive a non-HIV game and the Wisepill) on behavioral and biological measures. Information, Motivation, Behavioral Skills Adherence to ART Immersive iPhone Electronic, portable, 7-day medication game with text organizer/dispenser: measures adherence messaging integrates into iPhone gameHIV RNA Viral Load